U.S. patent application number 10/635659 was filed with the patent office on 2004-04-01 for preparation of aztreonam.
Invention is credited to Gyollai, Viktor, Meszaros Sos, Erzsebet, Salyi, Szabolcs, Singer, Claude, Szabo, Csaba.
Application Number | 20040063682 10/635659 |
Document ID | / |
Family ID | 31498630 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040063682 |
Kind Code |
A1 |
Gyollai, Viktor ; et
al. |
April 1, 2004 |
Preparation of aztreonam
Abstract
The invention relates to a process for the synthesis of
Aztreonam Specifically, the process entails hydrolyzing [3
S-[3.alpha.(Z),4.beta.]]-
-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl-
]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (t-Bu Aztreonam) to
form Aztreonam.
Inventors: |
Gyollai, Viktor; (Debrecen,
HU) ; Meszaros Sos, Erzsebet; (Debrecen, HU) ;
Szabo, Csaba; (Debrecen, HU) ; Singer, Claude;
(Kfar Saba, IL) ; Salyi, Szabolcs; (Debrecen,
HU) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
31498630 |
Appl. No.: |
10/635659 |
Filed: |
August 5, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60400699 |
Aug 5, 2002 |
|
|
|
60401749 |
Aug 8, 2002 |
|
|
|
Current U.S.
Class: |
514/210.2 ;
540/200 |
Current CPC
Class: |
C07D 417/12
20130101 |
Class at
Publication: |
514/210.2 ;
540/200 |
International
Class: |
C07D 417/02 |
Claims
What is claimed is:
1. A process for making Aztreonam comprising reacting
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl--
1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic
acid (t-Bu Aztreonam) with an aqueous acid.
2. The process of claim 1, wherein the acid is a mineral acid.
3. The process of claim 2, wherein the mineral acid is selected
from the group consisting of hydrochloric acid, sulfuric acid and
trifluoroacetic acid.
4. The process of claim 2, wherein the aqueous mineral acid has a
concentration greater than 0.1 mole/liter.
5. The process of claim 3, wherein the mineral acid is hydrochloric
acid.
6. The process of claim 3, wherein the mineral acid is
trifluoroacetic acid.
7. The process of claim 1, wherein the aqueous acid is a 1:1 v/v
HCl:water mixture.
8. The process of claim 1, wherein the reaction takes place at a
temperature greater than about 40.degree. C.
9. The process of claim 8, wherein the temperature is between about
50.degree. C. to about 80.degree. C.
10. The process of claim 9, wherein the temperature is between
about 60.degree. C. to about 70.degree. C.
11. The process of claim 1, wherein the yield of Aztreonam is at
least about 70%.
12. The process of claim 1, wherein the purity of Aztreonam, as
measured by HPLC, is greater than about 98%.
13. The process of claim 1, wherein the purity of Aztreonam, as
measured by HPLC, is greater than about 99%.
14. Aztreonam produced by the process of any of claims 1-10, which
has a purity as measured by HPLC, of greater than about 98%.
15. Aztreonam produced by the process of any of claims 1-10, which
is hydrated.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of provisional application Serial Number 60/400,699,
filed Aug. 5, 2002 and provisional application Serial Number
60/401,749, filed Aug. 8, 2002, both of which are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for the synthesis
of Aztreonam. Specifically, the process entails hydrolyzing
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[(1-t-butoxycarbonyl--
1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic
acid (t-Bu Aztreonam) to form Aztreonam.
BACKGROUND OF THE INVENTION
[0003] Aztreonam is a monobactam antibiotic disclosed in U.S. Pat.
No. 4,775,670, which is incorporated by reference herein in its
entirety. Aztreonam has the chemical name
(Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,-3S)--
2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methy-
lpropionic acid. Aztreonam is also known as
[3S-[3.alpha.(Z),4.beta.]]-3-[-
[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-met-
hyl-2-oxo-1-azetidinesulfonic acid and (2S,
3S)-3-[[2-[2-amino-4-thiazolyl-
]-(Z)-2[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-aze-
tidine-1-sulfonic acid.
[0004] Aztreonam has the structure: 1
[0005] Aztreonam is known to exist in various polymorphic forms
including the .alpha., .beta., .delta., and .gamma. forms.
[0006] U.S Pat. No. 4,775,670 discloses a process for making
Aztreonam, a compound of formula I: 2
[0007] The process includes acylating a compound of formula IV:
3
[0008] The acylation entails reacting a compound of formula IV with
a carboxylic acid or the corresponding carboxylic acid halide or
carboxylic acid anhydride (R.sub.1--OH) in the presence of a
carbodiimide such as dicyclohexylcarbodiimide and a substance
capable of forming an active ester in situ such as
N-hydroxybenzotriazole. U.S. Pat. No. 4,775,670 discloses that when
the acyl group (R.sub.1) contains reactive functional groups, such
as amino or carboxyl groups, it may be necessary to first protect
those functional groups, then carry out the acylation reaction, and
finally deprotect the resulting product. The deprotection is
carried out by reaction of the acylation product with
trifluoroacetic acid in the presence of anisole under anhydrous
conditions.
[0009] Similarly, U.S. Pat. No. 4,946,838 discloses a process for
making crystalline anhydrous Aztreonam comprising reacting the
diphenylmethyl ester of Aztreonam
([3S-[3.beta.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[(-
1-diphenylmethoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-ox-
o-1-azetidinesulfonic acid) with trifluoroacetic acid in the
presence of anisole under anhydrous conditions to produce the
.alpha.-form of Aztreonam. The .alpha.-form is recrystallized from
an anhydrous organic solvent to produce the .beta.-form of
Aztreonam. The .beta.-form is anhydrous, substantially
non-hygroscopic and more stable than the .alpha.-form.
[0010] U.S. Pat. No. 5,254,681 discloses a process for preparing
monobactams of formula (I): 4
[0011] wherein R is acyl. The process comprises acylating azetidin
with 2-(2-amino-4-thiazolyl)-2-(Z)-(alkoxyimino) acetic acid in the
presence of 1-hydroxy-benzotriazole and
dicyclohexylcarbodiimide.
[0012] U.S. Pat. No. 5,194,604 discloses a process and
intermediates for making beta-lactams having
aminothiazole(iminooxyacetic acid)acetic acid sidechains of formula
(I), such as Aztreonam. The process comprises acylating a compound
of formula III: 5
[0013] with a compound of formula (II): 6
[0014] in which R.sup.7 is 7
[0015] wherein 8
[0016] is a 4, 5, 6 or 7 membered heterocyclic ring having at least
one nitrogen atom in the ring or such a group fused to a phenyl or
substituted phenyl ring, to form a compound of formula (I): 9
[0017] wherein R.sub.1-R.sub.6 are as defined in U.S. Pat. No.
5,194,604.
[0018] U.S. Pat. No. 4,652,651, which is incorporated by reference
herein in its entirety, discloses a process for making
1-sulpho-2-oxoazetidine derivatives of the formula (I): 10
[0019] in which Het is an optionally amino-substituted, 5- or
6-membered, aromatic heterocycle containing 1 or 2 nitrogen atoms
and optionally also an oxygen or sulphur atom, R.sub.1 may be lower
alkoxycarbonyl-lower alkyl and R.sub.2 may be lower alkyl. The
process entails acylating a compound of formula (II): 11
[0020] in which R.sub.20 equals R.sub.2 and R.sub.3 is hydrogen or
sulpho, with a thioester of the formula (III): 12
[0021] in which Het is as above and R.sub.10 has any of the values
of R.sub.1. U.S. Pat. No. 4,652,651 discloses that where R10 is a
lower alkoxycarbonyl-lower alkyl group, for example the
t-butoxycarbonylmethyl group, this can be converted, if desired,
into the corresponding carboxylower alkyl group by treatment with a
strong acid such as trifluoroacetic acid (optionally in the
presence of anisole), hydrochloric acid or p-toluenesulphonic acid
at a low temperature such as -10.degree. C. to room
temperature.
[0022] There remains a need in the art for a process of making
Aztreonam which does not require anhydrous reaction conditions and
which also enables high yield and high purity. The present
invention answers this need.
SUMMARY OF THE INVENTION
[0023] The invention is based on the discovery that Aztreonam can
be produced by reacting
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)-
[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-a-
zetidinesulfonic acid with aqueous acid. The process of the
invention, enables yields of between 70-75% and purities above 98%,
preferably above 99%. The inventive aqueous process is advantageous
over the prior art anhydrous processes in that the reaction
conditions are more mild, there is no need to clean the final
product and there is no need to keep the system dry. Thus, the
aqueous process is less expensive than the anhydrous processes.
[0024] The present invention is directed to a process for preparing
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methyle-
thoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid
by hydrolyzing the ester group of
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4--
thiazolyl)[(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-
-2-oxo-1-azetidinesulfonic acid. The hydrolysis may be effected by
reacting the ester with aqueous acid, at elevated temperatures.
[0025] One reaction scheme for carrying out the process is shown
below: 13
DETAILED DESCRIPTION OF THE INVENTION
[0026] The invention is directed to a process for making Aztreonam
comprising reacting
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[-
(1-t-butoxycarbonyl-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-az-
etidinesulfonic acid also known as (t-Bu Aztreonam and Aztreonam
t-butyl ester) with an aqueous acid at elevated temperatures.
[0027] The aqueous acid is preferably a mineral acid, such as
hydrochloric acid or sulfuric acid, of various concentration. The
aqueous mineral acid is preferably more concentrated than 0.1
mol/l. Preferably, the aqueous acid is a 1:1 v/v HCl:water mixture.
Aqueous trifluoroacetic acid may also be used in various
concentrations.
[0028] The hydrolysis reaction is carried out at elevated
temperatures, preferably 40.degree. C. or greater, more preferably
between 50 and 80.degree. C., and most preferably between 60 and
70.degree. C.
[0029] The Aztreonam t-butyl ester can be obtained by reacting
Azetidin, (3S,4S)-3-Amino-4-methyl-2-oxo-azetidine-1-sulfonic acid,
with TAEM
((Z)-2-(2-Aminothiazole-4-yl)-2-(t-butoxycarbonyl)-isopropoxyimino
acetic acid, benzothiazole-2-yl-thiolester), as illustrated in
Examples 1 and 2.
[0030] The present invention is illustrated in further detail with
reference to the following non-limiting examples.
EXAMPLE 1
[0031] 5.4 g Azetidin is dissolved in 20 ml acetonitrile (or
dimethyl formamide) with the assistance of 5 ml of triethylamine at
room temperature. The solution is cooled to 0.degree. C. A solution
of 4 g TAEM in 25 ml THF is added with magnetic stirring. If the
color disappears, 8 g TAEM in 50 ml THF is added. After 10 minutes,
another 4.1 g TAEM in 25 ml THF is added. The solution is stirred
at 0.degree. C. for an additional hour. The pH is adjusted to about
4-5 with a freshly prepared TFA solution (TFA-THF 1:4, V/V). Being
careful not to evaporate the acetonitrile, the THF is evaporated
(weight loss is about 90 g) at 30.degree. C. under vacuum. The
remaining residue is diluted with 200 ml ethylacetate and then
extracted with 100 ml and then 50 ml of distilled water. The
aqueous extracts are combined and washed twice with 50 ml
ethylacetate after readjustment of the pH to about 4-5. The
dissolved ethylacetate is removed from the aqueous phase by vacuum
at 30.degree. C. 10-15 g KCl (or NaCl) is dissolved. The solution
is acidified with HCl solution (cc. HCl-distilled water 1:4, V/V)
with stirring (approx. 10 ml). The solution is cooled to 0.degree.
C. with slow stirring and crystallization occurs. The resulting
suspension is refrigerated overnight (at about 5.degree. C.). The
suspension is filtered on a glass filter, and the crystals are
washed with chilled water. The washed crystals are dried at room
temperature. The product, Aztreonam t-butyl ester, is about 12.5-13
g white solid, which is sufficiently pure for the next step.
EXAMPLE 2
[0032] 65 g Azetidine is dissolved in a mixture of 240 ml
acetonitrile and 60 ml triethylamine. When dissolution is complete,
TAEM is added in four portions. The suspension is stirred for 20-30
min, then diluted with 500 ml EtOAc and 500 ml water and stirred
for 5-10 min. The pH of the emulsion is set to 5 with 2.4 M HCl
solution. After the phases separate, the pH of the aqueous phase is
checked. If the pH is between 4.20 and 5.30, the two phases are
filtered and separated, otherwise more HCl is added. The upper
phase is diluted with 900 ml ethylacetate and extracted with
2.times.500 ml water (faster phase separation). The combined
aqueous phase is diluted with 500 ml water and washed with
2.times.500 ml ethylacetate. The dissolved ethylacetate is removed
from the aqueous phase by vacuum. The aqueous phase is acidified
further to pH 2 with 2.4 M HCl solution. The solution is stirred
and cooled. Crystallization starts soon. The suspension is stirred
and cooled to 0.degree. C., stirring at this temperature overnight.
The suspension is filtered, washed with chilled water, dried at
38.degree. C. in air-circulated oven for 3 h. The yield is approx.
116-120 g of Aztreonam t-butyl ester.
EXAMPLE 3
[0033] Aztreonam t-butyl ester (113.6 g, 0.231 mol) is suspended in
975 ml water at 60.degree. C. with stirring and 325 ml
trifluoroacetic acid is added. The solution is stirred for 60 min.,
then it is cooled slowly using an ice-water bath. After the product
precipitates, the suspension is refrigerated overnight. The product
is filtered on a glass-filter, suspended in 240 ml chilled water
and filtered again. The filtrate is re-suspended in 360 ml cold
acetone and filtered. The latter step is repeated and the product
is dried at room temperature to yield 61.6 g Aztreonam (water
content: 15-16%).
EXAMPLE 4
[0034] Aztreonam t-butyl ester (18.0 g, 0.0366 mol) is suspended in
144 ml water at 60.degree. C. with stirring and 40 ml aqueous
hydrochloric acid (1:1, V/V) is added. The solution is stirred for
60 min, then 37 ml 5.4 M NaOH solution is added. The solution is
cooled slowly using an ice-water bath. After the product
precipitates, the suspension is refrigerated overnight. The product
is filtered on a glass-filter, suspended in 50 ml chilled water and
filtered again. The filtrate is re-suspended in 70 ml cold acetone
and filtered. The latter step is repeated and the product is dried
at room temperature to yield 8.3 g Aztreonam (water content:
15-16%). The crude Aztreonam is crystallized.
EXAMPLE 5
[0035] Aztreonam t-butyl ester (100.00 g, Assay as is: 97.2%,
0.19796 mol)) is suspended in a mixture of 450 ml water and 5 ml
trifluoroacetic acid. The suspension, which slowly becomes clear,
is heated to 58.degree. C. with stirring and 100 ml trifluoroacetic
acid is added. The solution is stirred for 105 min at 60-63.degree.
C. The solution is added to chilled water (450 ml) with efficient
stirring and the resulting slurry is cooled further to 25.degree.
C. After two hours it is cooled to 0.degree. C. and stirred for 18
hours. The product is filtered on a glass-filter and washed with
300 ml chilled water. The product is suspended in 650 ml chilled
water, then filtered and washed with 300 ml cold acetone. The
product is suspended in 400 ml cold acetone and filtered and dried
in an air-ventilation oven at 30.degree. C. for 30 min. Yield: 66.6
g (63%, according to assays) Aztreonam (Assay: 100.5%, water
content: 18.0%).
[0036] HPLC Impurity Profile:
[0037] Aztreonam: 99.22%
[0038] Aztreonam t-butyl ester: 0.44%
[0039] HPLC Impurity Profile of Sample from Reaction Mixture:
[0040] Aztreonam: 82.20%
[0041] Aztreonam t-butyl ester: 0.43%
[0042] Aztreonam, open-chained: 7.22%
[0043] Other main degradation product (RRT=0.56): 5.24%
EXAMPLE 6
[0044] Aztreonam t-butyl ester (27.11 g, Assay as is: 96.5%,
0.05328 mol) is suspended in a mixture of 122 ml water and 1.35 ml
cc. HCl. The suspension is heated to 62.degree. C. with stirring
and 30 ml cc. HCl is added. The suspension, which becomes clear
after approx. 15 min, (then the product starts to precipitate), is
stirred for 30 min at 63-65.degree. C. Chilled water (162 ml) is
added with efficient stirring and the resulting slurry is cooled
further to 25.degree. C. After two hours it is cooled to 0.degree.
C. and stirred for 2 hours. The product is filtered on a
glass-filter, washed twice with 120 ml chilled water, twice with
125 ml cold acetone and filtered. The product is dried at room
temperature overnight. Yield: 19.44 g (72%, according to assays)
Aztreonam (Assay: 100.1%, water content: 14.4%).
[0045] HPLC Impurity Profile:
[0046] Aztreonam: 99.65%
[0047] Aztreonam t-butyl ester: 0.21%
[0048] HPLC Impurity Profile of Sample from Reaction Mixture:
[0049] Aztreonam: 89.43%
[0050] Aztreonam t-butyl ester: 0.26%
[0051] Aztreonam, open-chained: 4.70%
[0052] Other main degradation product (RRT=0.56): 1.47%
[0053] Having thus described the invention with reference to
particular preferred embodiments and illustrated it with examples,
those of skill in the art may appreciate modifications to the
invention as described and illustrated that do not depart from the
spirit and scope of the invention as disclosed in the
specification.
* * * * *